In a recent article published in the journal Nature Communications, researchers performed a large cross-sectional study to profile gut microbiota dysbiosis across prodromal and early stages of Parkinson’s disease (PD), REM sleep behavior disorder (RBD), first-degree relatives of RBD (RBD-FDR), and healthy controls.
Study: Gut microbiome dysbiosis across early Parkinson’s disease, REM sleep behavior disorder and their first-degree relatives. Image Credit: Anatomy Image / Shutterstock
PD, an alpha-synucleinopathy, typically manifests as the abnormal aggregation of alpha-synuclein (α-syn) protein in the central nervous system (CNS). Dream-enactment behaviors and REM sleep without atonia characterize RBD, the most specific prodromal marker of PD. Studies have confirmed that patients with video-polysomnography (v-PSG) diagnosed with RBD also suffer from constipation and α-syn pathology in ENS.
Strong scientific evidence suggests that before α-syn spreads to the CNS, α-syn pathology occurs in the enteric nervous system (ENS), which favors the gut-to-brain propagation of α-synucleinopathy. Since gut dysbiosis occurs in parallel, researchers have long hypothesized a correlation between pathological α-syn aggregation and PD-associated gut microbiota perturbations.
So, decades before motor symptoms of PD surface, constipation, the typical manifestation of a disturbed ENS due to α-syn aggregation, could indicate the onset of PD. It justifies why understanding gut microbiota and host–microbiome interactions at prodromal stages of PD are significant.
About the study
In the present study, researchers formed four study groups using 452 subjects, of which they retained only 441 with a high read count for further analyses. The first group comprised 178 people with v-PSG-diagnosed RBD patients. The 36 early PD patients had premotor RBD features and clinically confirmed PD; moreover, their motor symptoms had become apparent in the past five years.
The third group had 132 patients with RBD-FDR, and the fourth healthy control group comprised 130 individuals matched to people in RBD and early PD groups for age and gender. RBD patients had a greater likelihood ratio (LR) of prodromal PD than control and RBD-FDR, while controls and RBD-FDR groups had comparable levels of total LR. The team used the updated Movement Disorder Society (MDS) research criteria (2019) to compute LR and the probability of prodromal PD. A probability of prodromal PD > 80% and 30–80% were considered as probable and possible prodromal PD, respectively.
They used the RBD questionnaire Hong Kong (RBDQ-HK) to assess the severity of RBD features among all subjects exploring its dream-associated factors and behavioral manifestations. Likewise, the team used the Rome-IV diagnostic questionnaire to diagnose bowel disorders, e.g., functional constipation, diarrhea, and irritable bowel syndrome (IBS).
Additionally, the researchers documented stool consistency, bowel movement frequency score (BSFS), and some other gastrointestinal symptoms, e.g., dysphagia. They computed Parkinsonism using the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III), wherein a total score >three indicated subthreshold parkinsonism.
The team collected fresh stool samples for deoxyribonucleic acid (DNA) extraction and used a NanoDrop 2000 spectrophotometer to measure its concentrations. Finally, the team used random forest modeling to identify microbial markers that effectively distinguished RBD from controls.
Investigating gut microbiota across early PD, prodromal PD, i.e., RBD, RBD-FDR, and controls revealed that in RBD patients, the overall gut microbiota composition shifted to early PD, with depletion of butyrate-producing bacteria, and the overabundance of Desulfovibrio, Collinsella, and Oscillospiraceae UCG-005.
Note that Desulfovibrio is hydrogen sulfide (H2S) and lipopolysaccharide (LPS)-producing bacteria related to PD pathogenesis. The authors noted emerging PD-like microbial disturbances in younger RBD-FDR patients, e.g., increased pro-inflammatory Collinsella and decreased population of butyrate-producing Eubacterium.
The functional profile of gut microbiota dysbiosis showed an overall increase in fatty acid fermentation to lactate and ethanol. Similarly, it uncovered that during RBD-FDR, RBD, and early PD, levels of deazapurine biosynthesis reduced dramatically. Finally, the authors observed that host factors, such as bowel movement frequency, gender, age, and drug use, e.g., antidepressants, osmotic laxatives, or statins, partially confounded microbial alterations in early PD, RBD, and RBD-FDR.
On the contrary, at the prodromal stage and early α-synucleinopathy stage, apart from genera Akkermansia and Oscillospiraceae UCG-005, H2S-producing Desulfovibrio, and Collinsella increased in RBD patients. Intriguingly, the authors noted that adopting a high-fiber diet might reverse the disruption effect of mucin-degrading bacterial genera, e.g., Akkermansia. Clearly, dietary interventions at prodromal and early α-synucleinopathy, especially among patients with neurological disorders, such as anxiety and depression, could help improve their gut condition.
In this study, 16S ribosomal ribonucleic acid (RNA) gene sequencing data suggested increased fatty acids metabolism and reduced vitamin B12 and PreQ0 biosynthesis at prodromal and early α-synucleinopathy.
The latter is a key intermediate of biosynthesis of 7-deazapurine nucleoside, which helps in synthesizing several compounds with anti-cancer effects at prodromal and early α-synucleinopathy. PreQ0 biosynthesis consistently reduced at prodromal and early α-synucleinopathy. However, its abundance strongly co-occurs with Faecalibacterium, a butyrate-producing bacterial genus. It is also a biomarker of PD progression.
In PD patients, the authors observed the enrichment of lactic acid bacteria (LAB). Yet, the role of lactate in PD pathogenesis remains unclear, as it conflicts with the beneficial LAB effects. A possible justification is that other bacteria metabolize lactate and convert it to products that might disrupt the gut barrier.
Reduction in vitamin B12 biosynthesis or low serum B12 levels is a frequent indicator of early PD. However, B12 deficiency appears to be related to decreased dietary intake. Since vitamin B12 is a key modulator of gut microbiota, its supplementation could help reestablish gut health.
Taken together, the study data emphasized that gut dysbiosis is already present at a much earlier stage, preceding the onset of RBD and PD, reinstating its role in the pathogenesis of α-synucleinopathy. Future prospective studies, combined with investigations of gut composition, metabolism, and inflammatory markers, would further enlighten researchers about the role of gut microbiota in PD-related α-syn pathologies.
- Huang, B., Chau, S.W.H., Liu, Y., et al. Gut microbiome dysbiosis across early Parkinson’s disease, REM sleep behavior disorder, and their first-degree relatives. Nat Commun 14, 2501 (2023). DOI: https://doi.org/10.1038/s41467-023-38248-4, https://www.nature.com/articles/s41467-023-38248-4